The present invention relates to new benzodiazepine derivatives which can be orally administrated to exhibit a strong anticoagulant effect by reversibly inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral stroke, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral arterial occlusive disease; deep vein thrombosis; disseminated intravascular coagulation; thrombus formation after an artificial blood vessel-forming operation or an artificial valve substitution; reocclusion and restenosis after a coronary artery bypass grafting; reocclusion and restenosis after a reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like fibrinolytic therapy and antiplatelet therapy.
Thrombin inhibitors were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and aggregation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when thrombin inhibitors are orally administered, the bioavailability thereof is low. At present, no thrombin inhibitors which can be orally administered is available on the market.
Since the activated blood coagulation factor X is positioned at the juncture of an extrinsic coagulation cascade reaction and an intrinsic coagulation cascade reaction and in the upstream of thrombin, it is possible to inhibit the coagulation system more efficiently and specifically, than the thrombin inhibition, by inhibiting the factor X (Tidwell, R.; Webster, W. P.; Shaver, S. R.; Geratz, J. D. THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).
The object of the present invention is to provide compounds having an excellent effect of inhibiting the effect of activated blood coagulation factor X.
Another object of the present invention is to provide compounds having an effect of specifically inhibiting the effect of activated blood coagulation factor X, which can be orally administered.
Still another object of the present invention is to provide a pharmaceutical composition containing an above-described compound(s).
A further object of the present invention is to provide a blood-coagulation inhibitor or an agent for preventing or treating thrombosis or embolism, which contains one of the above-described compounds.
After intensive investigations made under these circumstances, the inventors have found that specified new benzodiazepine derivatives have an excellent effect of inhibiting activated blood coagulation factor X and are usable for preventing and treating various diseases caused by thrombi and emboli. The present invention has been completed on the basis of this finding.
Namely, the present invention provides benzodiazepine derivatives of following general formula (1) or pharmaceutically acceptable salts thereof: 
wherein ring A represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms or a cycloalkyl group having 4 to 10 carbon atoms,
R1 represents hydrogen atom, a halogeno group, hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethyl group, trifluoromethoxyl group, trifluoromethanesulfonyloxyl group, methylenedioxyl group, carbamoyl group, thiocarbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, a mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, an alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, a mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms, which may have a substituent(s), a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s), an arylsulfonyl group having 6 to 10 carbon atoms, which may have a substituent(s), a heteroarylsulfonyl group having 4 to 10 carbon atoms, which may have a substituent(s), an acyl group having 1 to 8 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms and substituted with an aryl group(s) having 6 to 10 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms and substituted with a heteroaryl group(s) having 5 to 10 carbon atoms, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), a heteroaryl group having 5 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), an amino group, which may have a substituent(s), an aminoalkyl group having 1 to 7 carbon atoms, which may have a substituent(s), pyrrolidine group, which may have a substituent(s), pyrrolidyloxyl group, which may have a substituent(s), piperidine group, which may have a substituent(s), piperidyloxyl group, which may have a substituent(s), piperazine group, which may have a substituent(s), piperazinecarbonyl group, which may have a substituent(s), amidino group, which may have a substituent(s) or guanidino group, which may have a substituent(s),
when R1 has a substituent(s), the substituent is any of alkyl groups having 1 to 6 carbon atoms, halogeno groups, hydroxyl group, alkoxyl groups having 1 to 10 carbon atoms, trifluoromethyl group, trifluoromethoxyl group, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amino group, aminoalkyl groups having 2 to 7 carbon atoms, mono- or dialkylamino groups having 1 to 6 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, tetraalkylamidino groups having 5 to 8 carbon atoms, guanidino group, dialkylguanidino groups having 3 to 8 carbon atoms, trialkylguanidino groups having 4 to 9 carbon atoms, aryl groups having 6 to 10 carbon atoms, heteroaryl groups having 1 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms and substituted with an aryl group(s) having 6 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms and substituted with a heteroaryl group(s) having 5 to 10 carbon atoms, aryl groups having 6 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, heteroaryl groups having 5 to 10 carbon atoms and substituted with an alkyl group(s) having 1 to 6 carbon atoms, arylsulfonyl groups having 6 to 10 carbon atoms, heteroarylsulfonyl groups having 4 to 10 carbon atoms, carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, pyrrolidine group, piperidine group, piperazine group, piperazinecarbonyl group, alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, piperidyloxyl group, alkylpiperidyloxyl groups having 6 to 10 carbon atoms, iminoalkylpiperidyloxyl groups having 7 to 10 carbon atoms, pyrrolidyloxyl group, alkylpyrrolidyloxyl groups having 6 to 10 carbon atoms, iminoalkylpyrrolidyloxyl groups having 7 to 10 carbon atoms, methylenedioxyl group, cyano group, iminoalkyl groups having 2 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 6 carbon atoms, aminosulfonyl group and dialkylaminosulfonyl groups having 2 to 8 carbon atoms,
rings B and C may be the same or different from each other, and they each represent an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, pyrrolidyl group, piperidyl group or piperazinyl group,
R2 represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethoxyl group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, a mono- or dialkylamino group having 1 to 6 carbon atoms, an aminoalkyl group having 2 to 9 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms, a trialkylamidino group having 4 to 7 carbon atoms, a tetraalkylamidino group having 5 to 8 carbon atoms, guanidino group, a dialkylguanidino group having 3 to 8 carbon atoms, a trialkylguanidino group having 4 to 9 carbon atoms, methylenedioxyl group, cyano group, an iminoalkyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, piperidyloxyl group, an alkylpiperidyloxyl group having 6 to 10 carbon atoms, an iminoalkylpiperidyloxyl group having 6 to 10 carbon atoms, an alkoxycarbonylpiperidyloxyl group having 8 to 14 carbon atoms, pyrrolidyloxyl group, an alkylpyrrolidyloxyl group having 5 to 9 carbon atoms, an iminoalkylpyrrolidyloxyl group having 5 to 9 carbon atoms, an alkoxycarbonylpyrrolidyloxyl group having 7 to 13 carbon atoms, pyrrolidine group, an alkylpyrrolidine group having 5 to 9 carbon atoms, an iminoalkylpyrrolidine group having 5 to 9 carbon atoms, piperidine group, an alkylpiperidine group having 6 to 10 carbon atoms, an iminoalkylpiperidine group having 6 to 10 carbon atoms, piperazine group, an alkylpiperazine group having 5 to 13 carbon atoms, an iminoalkylpiperazine group having 6 to 9 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonyl group having 4 to 10 carbon atoms, an iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, piperazinesulfonyl group, an alkylpiperazinesulfonyl group having 5 to 9 carbon atoms, an iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, aminosulfonyl group, a mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, a piperidylalkyl group having 6 to 9 carbon atoms or an iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms,
R3 represents hydrogen atom, a halogeno group, hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethyl group, trifluoromethoxyl group, carbamoyl group, thiocarbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, methylenedioxyl group, cyano group, an iminoalkyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, piperidyloxyl group, an iminoalkylpiperidyloxyl group having 6 to 10 carbon atoms, an alkylpiperidyloxyl group having 5 to 10 carbon atoms, an alkoxycarbonylpiperidyloxyl group having 8 to 14 carbon atoms, pyrrolidyloxyl group, an iminoalkylpyrrolidyloxyl group having 5 to 9 carbon atoms, an alkylpyrrolidyloxyl group having 5 to 10 carbon atoms, an alkoxycarbonylpyrrolidyloxyl group having 7 to 13 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonyl group having 4 to 10 carbon atoms, an iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, an iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an amino group, which may have a substituent(s), an aminoalkyl group having 2 to 9 carbon atoms, which may have a substituent(s), pyrrolidine group, which may have a substituent(s), piperidyl group, which may have a substituent(s), a piperazine group, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms, which may have a substituent(s), a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s), an aryl group having 6 to 10 carbon atoms, which is substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), a heteroaryl group having 5 to 10 carbon atoms, which is substituted with an alkyl group(s) having 1 to 6 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms, substituted with an aryl group(s) having 6 to 10 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms, substituted with a heteroaryl group(s) having 5 to 10 carbon atoms, which may have a substituent(s), an amidino group, which may have a substituent(s), a guanidino group, which may have a substituent(s), a piperidylalkyl group having 6 to 9 carbon atoms or an iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms,
when R3 has a substituent(s), the substituent is any of hydrogen atom, alkyl groups having 1 to 6 carbon atoms, halogeno groups, hydroxyl group, hydroxyalkyl groups having 1 to 10 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, alkoxyalkyl groups having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethoxyl group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amino group, mono- or dialkylamino groups having 1 to 6 carbon atoms, aminoalkyl groups having 2 to 9 carbon atoms, mono- or dialkylaminoalkyl groups having 2 to 9 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, tetraalkylamidino groups having 5 to 8 carbon atoms, guanidino group, dialkylguanidino groups having 3 to 8 carbon atoms, trialkylguanidino groups having 4 to 9 carbon atoms, methylenedioxyl group, cyano group, iminoalkyl groups having 2 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, piperidyloxyl group, alkylpiperidyloxyl groups having 6 to 10 carbon atoms, iminoalkylpiperidyloxyl groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxyl groups having 8 to 14 carbon atoms, pyrrolidyloxyl group, alkylpyrrolidyloxyl groups having 5 to 9 carbon atoms, iminoalkylpyrrolidyloxyl groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxyl groups having 7 to 13 carbon atoms, pyrrolidine group, alkylpyrrolidine groups having 5 to 9 carbon atoms, iminoalkylpyrrolidine groups having 5 to 9 carbon atoms, piperidine group, alkylpiperidine groups having 6 to 10 carbon atoms, iminoalkylpiperidine groups having 6 to 10 carbon atoms, piperazine group, alkylpiperazine groups having 5 to 13 carbon atoms, iminoalkylpiperazine groups having 6 to 9 carbon atoms, aryl groups having 6 to 10 carbon atoms, heteroaryl groups having 1 to 10 carbon atoms, arylsulfonyl groups having 6 to 10 carbon atoms, heteroarylsulfonyl groups having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms, piperazinesulfonyl group, alkylpiperazinesulfonyl groups having 5 to 9 carbon atoms, iminoalkylpiperazinesulfonyl groups having 6 to 9 carbon atoms, alkylsulfonyl groups having 1 to 8 carbon atoms, aminosulfonyl group and mono- or dialkylaminosulfonyl groups having 2 to 8 carbon atoms,
R4, R5, R6, R7, R8 and R9 may be the same or different from one another, and they each represent hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, trifluoromethoxyl group, trifluoromethyl group, amino group, a mono- or dialkylamino group having 1 to 6 carbon atoms, an aminoalkyl group having 2 to 9 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, methylenedioxyl group, cyano group, formyl group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 9 carbon atoms, a hydroxycarbonylalkyl group having 3 to 9 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, an alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, a phosphorylalkyl group having 1 to 9 carbon atoms, a dialkoxyphosphorylalkyl group having 3 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl alkyl group having 2 to 9 carbon atoms, 2-carboxy-2-oxoethyl group or a heteroaryl group having 1 to 10 carbon atoms,
X represents an alkylene group having 1 to 6 carbon atoms, which may contain xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O), xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94 or xe2x80x94NHC(xe2x95x90O)NHxe2x80x94 in its chain, and
Z1 and Z2 may be the same or different from each other, and they each represent hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, hydroxyl group, a hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, a thioalkyl group having 1 to 6 carbon atoms, an alkylthioalkyl group having 2 to 8 carbon atoms, a carbamoylalkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, which is substituted with an alkyl group(s) having 1 to 6 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, which is substituted with an alkyl group(s) having 1 to 6 carbon atoms, an aminoalkyl group having 1 to 6 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, a hydroxycarbonylalkyl group having 2 to 8 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbon atoms, an aminoalkyl group having 1 to 6 carbon atoms or a mono- or dialkylaminoalkyl group having 2 to 10 carbon atoms, or Z1 and Z2 together form a ring and in such a case, -Z1-Z2- represents ethylene group, trimethylene group or tetramethylene group.
The present invention also provides benzodiazepine derivatives of the above general formula (1) or pharmaceutically acceptable salts of them, wherein ring A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R1 represents hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, hydroxyl group, a hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, nitro group, trifluoromethyl group, trifluoromethoxyl group, carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, an aminoalkyl group having 1 to 3 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a hydroxycarbonylalkyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbon atoms, a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms, an alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms or a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms,
ring B represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, piperidyl group or piperazine group,
R2 and R3 may be the same or different from each other, and they each represent hydrogen atom (only for R2), a halogeno group, an alkyl group having 1 to 6 carbon atoms, hydroxyl group, a hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, nitro group, trifluoromethyl group, trifluorometoxyl group, carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, an aminoalkyl group having 1 to 3 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms, guanidino group, a dialkylguanidino group having 3 to 8 carbon atoms, methylenedioxyl group, cyano group, an iminoalkyl group having 2 to 7 carbon atoms, acetyl group, piperidyloxyl group, an iminoalkylpiperidyloxyl group having 6 to 10 carbon atoms, an alkoxycarbonylpiperidyloxyl group having 8 to 14 carbon atoms, pyrrolidyloxyl group, an iminoalkylpyrrolidyloxyl group having 5 to 9 carbon atoms, an alkoxycarbonylpyrrolidyloxyl group having 7 to 13 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonyl group having 4 to 10 carbon atoms, an arylalkyl group having 5 to 12 carbon atoms, a heteroarylalkyl group having 5 to 12 carbon atoms, an iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, an iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, a piperidylalkyl group having 6 to 9 carbon atoms or an iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms,
ring C represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 4 to 10 carbon atoms, piperidyl group or piperazine group, R4, R5, R6, R7, R8 and R9 each represent hydrogen atom,
X represents an alkyl group having 1 to 6 carbon atoms, which may contain xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94 or xe2x80x94NHC(xe2x95x90O)NHxe2x80x94 in its chain, and
Z1 and Z2 each represent hydrogen atom.
The present invention provides an activated blood coagulation factor X inhibitor containing one of the above-described benzodiazepine derivatives or a pharmaceutically acceptable salt thereof as the active ingredient.
The present invention also provides a pharmaceutical composition containing the above-described benzodiazepine derivatives or a pharmaceutically acceptable salt thereof as the active ingredient.
The present invention further provides a blood coagulation inhibitor or an agent for preventing or treating thrombosis or embolism, which contains one of the above-described benzodiazepine derivatives or a pharmaceutically acceptable salt thereof as the active ingredient.
In this specification, aryl groups indicate aromatic cyclic hydrocarbon groups having 6 to 10 carbon atoms such as phenyl group, 1-naphthyl group and 2-naphthyl group. Among them, phenyl group is preferred.
Unless otherwise stated, the term xe2x80x9carylxe2x80x9d in the arylsulfonyl groups or the like in this specification will be the same as the xe2x80x9carylxe2x80x9d described above.
The term heteroaryl group indicates aromatic cyclic hydrocarbon group having 1 to 10 carbon atoms and 1 to 3 hetero atoms selected from the group consisting of O, N and S. Concretely, they are pyridyl group, pyrimidyl group, pyridazinyl group, pyrazinyl group, imidazolyl group, pyrrolyl group, thiophene group, pyrazyl group, pyrazolyl group, pyrrolyl group, triazyl group, furyl group, isoxazolyl group, isothiazolyl group, indolyl group, quinolyl group, isoquinolyl group, tetrazole group, etc. Among them, heteroaryl groups having 4 to 10 carbon atoms and 1 or 2 N and/or S as the hetero atom are preferred, and pyridyl group and thiophene group are particularly preferred.
Unless otherwise stated, the term xe2x80x9cheteroarylxe2x80x9d in the heteroarylsulfonyl groups or the like in this specification will be the same as the xe2x80x9cheteroarylxe2x80x9d described above.
The term alkyl group indicates linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms. In the alkyl groups, those having 1 to 3 carbon atoms are preferred. Concretely, they are methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, sec- and tert-butyl groups, n-pentyl group, i-pentyl group, tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, etc. Among them, methyl group, ethyl group, n-propyl group and i-propyl group are preferred.
The cyclic alkyl groups are alkyl groups having 4 to 10 carbon atoms. Those having 5 or 6 carbon atoms are preferred. Concretely, they are cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc. Among them, cyclopentyl group and cyclohexyl group are preferred. Cyclohexyl group is particularly preferred.
Unless otherwise stated, the term xe2x80x9calkylxe2x80x9d in the hydroxyalkyl groups and iminoalkyl groups or the like in this specification will be the same as the xe2x80x9calkylxe2x80x9d described above.
The alkenyl groups are linear or branched alkenyl groups having 2 to 6 carbon atoms. Concretely, they are vinyl group, propenyl group, 2-methyl-1-propenyl group, etc.
Unless otherwise stated, the term xe2x80x9calkenylxe2x80x9d in the hydroxycarbonylalkenyl groups, alkoxycarbonylalkenyl groups, etc. in this specification will be the same as the xe2x80x9calkenylxe2x80x9d described above.
The halogeno groups include fluorine atom, chlorine atom, bromine atom and iodine atom. Among them, chlorine atom and bromine atom are preferred.
The alkoxyl groups are linear or branched alkoxyl groups having 1 to 10 carbon atoms, alkoxyl groups having a cycloalkyl groups and 4 to 10 carbon atoms and alkoxyl groups having a fused cyclic carbon chain ring system. Concretely, they are methoxyl group, ethoxyl group, n-propoxyl group, isopropoxyl group, n-butoxyl group, i-butoxyl group, sec-butoxyl group, tert-butoxyl group, benzyloxyl group, 2-phenylethoxyl group, 3-phenylpropyloxyl group, 4-phenylbutoxyl group, 5-phenylpentyloxyl group, 6-phenylhexyloxyl group, cyclopropyloxyl group, cyclobutoxyl group, cyclopentyloxyl group, cyclohexyloxyl group, 1-indanyloxyl group and 2-indanyloxyl group, etc. Among them, methoxyl group, ethoxyl group and n-propoxyl group are preferred.
Unless otherwise stated, the term xe2x80x9calkoxylxe2x80x9d in the alkoxyalkyl groups, alkoxycarbonylpiperidyloxyl groups, etc. in this specification will be the same as the xe2x80x9calkoxylxe2x80x9d described above.
The mono- or dialkylcarbamoyl groups include monoalkylcarbamoyl groups such as methylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group and i-propylcarbamoyl group, and dialkylcarbamoyl groups such as dimethylcarbamoyl group, diethylcarbamoyl group, di(n-propyl)carbamoyl group and di(i-propyl)carbamoyl group, etc. The chain length of the two alkyl groups in the dialkylcarbamoyl group may be different from each other. The two alkyl groups in the dialkylcarbamoyl group may be bonded together to form a ring or they may form a ring containing an unsaturated hydrocarbon group. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include 1-pyrrolidinecarbonyl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, 1-piperidinecarbonyl group, 1-piperazinecarbonyl group, (morpholin-4-yl)carbonyl group and (thiomorpholin-4-yl)carbonyl group, etc. In these groups, dimethylcarbamoyl group, 1-pyrrolidinecarbonyl group, (morpholin-4-yl)carbonyl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group and (thiomorpholin-4-yl)carbonyl group are preferred.
The mono- or dialkylamino groups having 1 to 6 carbon atoms include monoalkylamino groups such as methylamino group, ethylamino group, n-propylamino group and i-propylamino group, etc, and dialkylamino groups such as dimethylamino group, diethylamino group, di(n-propyl)amino group and di(i-propyl)amino group, etc. The chain length of the two alkyl groups in the dialkylamino group may be different from each other. The two alkyl groups in the dialkylamino group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include pyrrolidinyl group, piperidinyl group, morpholinyl group and thiomorpholinyl group, etc. In these groups, morpholinyl group and thiomorpholinyl group are preferred.
The alkoxycarbonyl groups having 2 to 7 carbon atoms include, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, sec-butoxycarbonyl group and tert-butoxycarbonyl group, etc. In these groups, methoxycarbonyl group and ethoxycarbonyl group are preferred.
The dialkoxyphosphoryl groups having 2 to 9 carbon atoms include, for example, diethoxyphosphoryl group, di(n-propoxy)phosphoryl group, di(isopropoxy)phosphoryl group, di(n-butoxy)phosphoryl group, di(i-butoxy)phosphoryl group, di(sec-butoxy)phosphoryl group and di(tert-butoxy)phosphoryl group, etc. In these groups, diethoxyphosphoryl group is preferred.
The monoalkoxyhydroxyphosphoryl groups include, for example, monomethoxyhydroxyphosphoryl group, monoethoxyhydroxyphosphoryl group, mono-n-propoxyhydroxyphosphoryl group, monoisopropoxyhydroxyphosphoryl group, mono-n-butoxyhydroxyphosphoryl group, mono-i-butoxyhydroxyphosphoryl group, mono-sec-butoxyhydroxy-phosphoryl group and mono-tert-butoxyhydroxyphosphoryl group, etc. In these groups, monoethoxyhydroxyphosphoryl group is preferred.
The alkylsulfonyl groups include, for example, methylsulfonyl group, ethylsulfonyl group, sulfonyl group, n-propylsulfonyl group and i-propylsulfonyl group, etc. In these groups, methylsulfonyl group is preferred.
The mono- or dialkylaminosulfonyl groups include monoalkylaminosulfonyl groups such as methylaminosulfonyl group, ethylaminosulfonyl group, n-propylaminosulfonyl group and i-propylaminosulfonyl group, etc. and dialkylaminosulfonyl groups such as dimethylaminosulfonyl group, diethylaminosulfonyl group, di(n-propyl)aminosulfonyl group and di(i-propyl)aminosulfonyl group, etc. The chain length of the two alkyl groups in the dialkylaminosulfonyl group may be different from each other. The two alkyl groups in the dialkylaminosulfonyl group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include (pyrrolidin-1-yl)sulfonyl group, (piperidin-1-yl)sulfonyl group, (morpholin-4-yl)sulfonyl group and (thiomorpholin-4-yl)sulfonyl group, etc. In these groups, (pyrrolidin-1-yl)sulfonyl group is preferred.
The acyl groups include, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group and pivaloyl group, etc.
The aminoalkyl groups include, for example, aminomethyl group, 2-aminoethyl group, 2-aminopropyl group and 3-aminopropyl group, etc. In these groups, aminoalkyl groups having 1 to 7 carbon atoms, particularly 3-aminopropyl group, is preferred.
The mono- or dialkylamidino groups include monoalkylamidino groups such as methylamidino group and ethylamidino group, and dialkylamidino group such as dimethylamidino group and diethylamidino group. The chain length of the two alkyl groups in the dialkylamidino group may be different from each other. The two alkyl groups in the dialkylamidino group may be bonded together to form a ring or they may form a ring containing an unsaturated hydrocarbon group. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include (pyrrolidin-1-yl)(imino)methyl group, (piperidin-1-yl)(imino)methyl group, 1,4,5,6-tetrahydro-2-pyrimidinyl group, (morpholin-4-yl)(imino)methyl group, 2,5-dihydro-1 H-pyrrol-1-yl(imino)methyl group and (thiomorpholin-4-yl)(imino) methyl group, etc. In these groups, 2,5-dihydro-1H-pyrrol-1-yl(imino)methyl group, dimethylamidino group, (pyrrolidin-1-yl)(imino)methyl group and (thiomorpholin-4-yl)(imino)methyl group are preferred.
The trialkylamidino groups include trimethylamidino group, triethylamidino group, tri(n-propyl)amidino group and tri(i-propylamidino) group, etc. The chain length of the three alkyl groups in the trialkylamidino group may be different from each other. Two of the three alkyl groups in the trialkylamidino group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include 1-methyl-1H-imidazol-2-yl group and 1-ethyl-1H-imidazol-2-yl group, etc. In these groups, 1-methyl-1H-imidazol-2-yl group is preferred.
The tetraalkylamidino groups having 5 to 8 carbon atoms include, for example, (dimethylamino)(dimethyl iminio)methyl group, etc. The chain length of the four alkyl groups in the tetraalkylamidino group may be different from each other. Two of the four alkyl groups in the tetraalkylamidino group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group and 1-ethyl-3-methyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group, etc. In these groups, 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group is preferred.
The dialkylguanidino groups include, for example, dimethylguanidino group, diethylguanidino group, di(n-propyl)guanidino group and di(i-propyl)guanidino group, etc. The chain length of the two alkyl groups in the dialkylguanidino groups may be the same or different from each other. Two alkyl groups in the dialkylguanidino group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include imidazoline-2-amino group, etc.
The trialkylguanidino groups include, for example, trimethylguanidino group, triethylguanidino group, tri(n-propyl)guanidino group and tri(i-propyl)guanidino group, etc. The chain length of the three alkyl groups in the trialkylguanidino groups may be the same or different from each other. Two alkyl groups in the trialkylguanidino group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include 1-methyl-2-imidazolin-2-yl-amino group, 1-ethyl-2-imidazolin-2-yl-amino group, 1-(n-propyl)-2-imidazolin-2-yl-amino group and 1-(i-propyl)-2-imidazolin-2-yl-amino group, etc. In these groups, 1-methyl-2-imidazolin-2-yl-amino group is preferred.
The alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms include, for example, methylpiperazinecarbonyl group, ethylpiperazinecarbonyl group, n-propylpiperazinecarbonyl group, i-propylpiperazinecarbonyl group, n-butylpiperazinecarbonyl group, i-butylpiperazinecarbonyl group, sec-butylpiperazinecarbonyl group and tert-butylpiperazinecarbonyl group, etc. In these groups, i-propylpiperazinecarbonyl group is preferred.
The mono- or dialkylaminoalkyl groups include monoalkylaminoalkyl groups such as methylaminomethyl group, methylaminoethyl group, methylaminopropyl group, ethylaminomethyl group, ethylaminoethyl group, ethylaminopropyl group, n-propylaminomethyl group, n-propylaminoethyl group, n-propylaminopropyl group, i-propylaminomethyl group, i-propylaminoethyl group and i-propylaminopropyl group, etc. and dialkylaminoalkyl groups such as dimethylaminomethyl group, dimethylaminoethyl group, dimethylaminopropyl group, diethylaminomethyl group, diethylaminoethyl group, diethylaminopropyl group, di(n-propyl)aminomethyl group, di(n-propyl)aminoethyl group, di(n-propyl)aminopropyl group, di(i-propyl)aminomethyl group, di(i-propyl)aminoethyl group and di(i-propyl)aminopropyl group, etc. The chain length of the three alkyl groups in the dialkylaminoalkyl groups may be the same or different from each other. Two alkyl groups in the dialkylaminoalkyl group may be bonded together to form a ring. In this case, one of xe2x80x94CH2xe2x80x94 groups may be replaced with O, NH or S. Concretely, they include, for example, (pyrrolidin-1-yl)methyl group, (pyrrolidin-1-yl)ethyl group, (pyrrolidin-1-yl)propyl group, (piperidin-1-yl)methyl group, (piperidin-1-yl)ethyl group, (piperidin-1-yl)propyl group, (morpholin-4-yl)methyl group, (morpholin-4-yl)ethyl group, (morpholin-4-yl)propyl group, (thiomorpholin-1-yl)methyl group, (thiomorpholin-1-yl)ethyl group and (thiomorpholin-1-yl)propyl group, etc.
Ring A in the above general formula (1) is preferably an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 10 carbon atoms (particularly a heteroaryl group having 4 to 10 carbon atoms, more particularly, a heteroaryl group having 3 to 5 carbon atoms). A cycloalkyl group having 5 or 6 carbon atoms is also preferred. In these groups, phenyl group, pyridyl group, pyrazolyl group and cyclohexyl group are preferred. Phenyl group is particularly preferred.
R1 is preferably hydrogen atom, a halogeno group, hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, trifluoromethyl group, trifluoromethanesulfonyloxyl group, carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, a mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an aminoalkyl group having 2 to 7 carbon atoms, which may have a substituent(s), piperazinecarbonyl group, which may have a substituent(s) and amidino group, which may have a substituent(s). In these groups, hydrogen atom, chloro group, carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, amino group, which may have a substituent(s), hydroxyl group, which may have a substituent(s) and alkyl groups having 1 to 6 carbon atoms are preferred.
When R1 has a substituent(s), the substituent is preferably an alkyl group having 1 to 6 carbon atoms, hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, pyrrolidine group, piperidine group, piperazine group, piperazinecarbonyl group, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms or dialkylamidino group.
The substituent is more preferably hydroxyl group, phosphono group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, piperazinecarbonyl group, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms.
R1 is more preferably hydrogen atom, chloro group, amino group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, a morpholinealkyl group, hydroxyl group, methyl group, phosphonoethyl group, morpholinecarbonylethyl group, piperazinecarbonylethyl group, isopropylpiperazinecarbonylethyl group, methanesulfonylaminopropyl group or hydroxypropyl group.
R4 and R5 are each preferably hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group. It is particularly preferred that both R4 and R5 are hydrogen atom.
R1, R4 and R5 may be the same or different from one another. It is particularly preferred that when ring A is phenyl group, R1 is bonded to the phenyl group at the 7- and/or 8-position.
X is preferably an alkylene group having 1 to 6 carbon atoms, more preferably a linear alkylene group having 1 to 3 carbon atoms, and still more preferably methylene group or ethylene group. X is particularly preferably methylene group. The group contained in the chain of the alkylene group X is preferably xe2x80x94C(xe2x95x90O)NHxe2x80x94 or xe2x80x94NHC(xe2x95x90O)xe2x80x94. xe2x80x94C(xe2x95x90O)NHxe2x80x94 is particularly preferred.
Ring B is preferably an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms (particularly a heteroaryl group having 4 to 10 carbon atoms), piperidyl group or piperazine group. The aryl groups are preferably phenyl group and 2-naphthyl group. The heteroaryl groups are preferably thiophene group and pyridyl group. The aryl groups having 6 to 10 carbon atoms and the heteroaryl groups having 4 to 10 carbon atoms are particularly preferred. Further, phenyl group, naphthyl group, pyridyl group, thiophene group and piperidyl group are preferred. Phenyl group and thiophene group are more preferred.
R2 is preferably a halogeno group, particularly chloro group or bromo group; an alkoxyl group having 1 to 10 carbon atoms, particularly an alkoxyl group having 1 to 3 carbon atoms, and particularly methoxyl group; an alkyl group having 1 to 6 carbon atoms, particularly methyl group or ethyl group; or trifluoromethyl group. The halogeno group, particularly chloro group or bromo group is the most preferred.
R6 and R7 may be the same or different from each other, and preferably, they are each hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group. It is more preferred that both R6 and R7 are hydrogen atoms.
R2, R6 and R7 may be the same or different from one another. Preferably, when ring B is phenyl group, R2 is bonded to the phenyl group at the 3- and/or 4-position; when ring B is thienyl group, R2 is bonded to the thienyl group at the 5-position; when ring B is pyridyl group, R2 is bonded to the thienyl group at the 5-position; and when ring B is piperidyl group, R2 is bonded to the piperidyl group at the 1-position.
It is particularly preferred that ring B is phenyl group, R2 is bonded to the phenyl ring at the 4-position and both R6 and R7 are hydrogen atoms.
Ring C is preferably an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 6 carbon atoms. Ring C is also preferably piperidyl group. The aryl group is preferably phenyl group. The heteroaryl group is preferably pyridyl group or quinolyl group. Ring C is particularly preferably phenyl group or piperidyl group (particularly 4-piperidyl group).
R3 is preferably a halogeno group, nitro group, an iminoalkyl group having 2 to 7 carbon atoms, piperidyloxyl group, an iminoalkylpiperidyloxyl group having 6 to 10 carbon atoms, an alkylpiperidyloxyl group having 5 to 10 carbon atoms, amino group, which may have a substituent(s), an aminoalkyl group having 2 to 9 carbon atoms, which may have a substituent(s), pyrrolidine group, which may have a substituent(s), piperazine group, which may have a substituent(s), a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s) or amidino group, which may have a substituent(s). R3 is more preferably a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s) or an amidino group, which may have a substituent(s). R3 is also preferably a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s), particularly pyridyl group (particularly 4-pyridyl group). R3 is particularly preferably an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), a halogeno group, pyridyl group (particularly 4-pyridyl group), nitro group, amino group, dialkylamino group, amidino group, which may have a substituent(s) or piperidyloxyl group, which may have a substituent(s).
When R3 has a substituent(s), the substituent is preferably any of hydrogen atom, alkyl groups having 1 to 6 carbon atoms, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, mono- or dialkylaminoalkyl groups having 2 to 9 carbon atoms, mono- or dialkylamidino groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, pyrrolidine group, piperidine group, alkylsulfonyl groups having 1 to 8 carbon atoms and pyridyl group. In these groups, the alkyl groups having 1 to 6 carbon atoms and pyridyl group are more preferred.
R3 is more preferably any of isopropyl group, cyclohexyl group, pyridyl group, 1-methyl-1H-imidazol-2-yl group, 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, 1-pyrrolidinylcarbonyl group, 2,5-dihydro-1H-pyrrol-1-yl(imino)methyl group and 1-iminoethyl-piperidin-4-yloxyl group.
R8 and R9 may be the same or different from each other, and preferably they are each hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group. It is also preferred that R8 and R9 are each hydrogen atom, a halogeno group or pyridyl group.
The positions of R3, R8 and R9 are not particularly limited. However, it is particularly preferred that when ring C is phenyl group, R3 is bonded to the phenyl group at the 4-position; when ring C is pyridyl group, R3 is bonded to the pyridyl group at the 3-position; and when ring C is piperidyl group, R3 is bonded to the piperidyl group at the 1-position. It is particularly preferred that ring C is piperidyl group, R3 is bonded to the piperidyl group at the 4-position and R8 and R9 are each hydrogen atom.
X is preferably an alkylene group having 1 to 6 carbon atoms. X is also preferably an alkylene group having 1 to 3 carbon atoms, which may contain xe2x80x94C(xe2x95x90O)NHxe2x80x94 in its chain. X is more preferably methylene group or ethylene group. X is particularly preferably methylene group.
Z1 and Z2 may be the same or different from each other. It is preferred that they are each hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms. It is particularly preferred that both Z1 and Z2 are hydrogen atom.
It is preferred that in general formula (1), ring A represents an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms,
R1 represents hydrogen atom, a halogeno group, hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, trifluoromethyl group, trifluoromethanesulfonyloxyl group, carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, a mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an aminoalkyl group having 2 to 7 carbon atoms, which may have a substituent(s), piperazinecarbonyl group, which may have a substituent(s) or amidino group, which may have a substituent(s),
when R1 has a substituent(s), the substituent is any of alkyl groups having 1 to 6 carbon atoms, hydroxyl group, mono- or dialkylamino groups having 1 to 6 carbon atoms, heteroaryl groups having 1 to 10 carbon atoms, carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, pyrrolidine group, piperidine group, piperazine group, piperazinecarbonyl group, alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms, phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 6 carbon atoms and dialkylamidino groups having 1 to 6 carbon atoms, and
R4 and R5 are both hydrogen atom.
It is also preferred that in general formula (1), ring A represents phenyl group,
R1 represents hydrogen atom, chloro group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an amino group, which may have a substituent(s), hydroxyl group, which may have a substituent or an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s),
when R1 has a substituent(s), the substituent is hydroxyl group, phosphono group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 6 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, piperazinecarbonyl group, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms, and
R4 and R5 may be the same or different from each other and they each represent hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group.
It is also preferred that in general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 represents chloro group or bromo group, and
R6 and R7 may be the same or different from each other and they each represent hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group.
It is also preferred that in general formula (1), ring C represents an aryl group having 6 to 10 carbon atoms or piperidyl group,
R3 represents a halogeno group, nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, piperidyloxyl group, an iminoalkylpiperidyloxyl group having 6 to 10 carbon atoms, an alkylpiperidyloxyl group having 5 to 10 carbon atoms, an amino group, which may have a substituent(s), an aminoalkyl group having 2 to 9 carbon atoms, which may have a substituent(s), an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), pyrrolidine group, which may have a substituent(s), piperazine group, which may have a substituent(s), a heteroaryl group having 1 to 10 carbon atoms, which may have a substituent(s), or an amidino group, which may have a substituent(s),
when R3 has a substituent(s), the substituent is hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, a mono- or dialkylamidino group having 2 to 7 carbon atoms, a trialkylamidino group having 4 to 7 carbon atoms, pyrrolidine group, piperidine group, an alkylsulfonyl group having 1 to 8 carbon atoms or pyridyl group,
R8 and R9 may be the same or different from each other and each represent hydrogen atom, a halogeno group or pyridyl group, and
X represents an alkylene group having 1 to 3 carbon atoms, which may contain xe2x80x94C(xe2x95x90O)NHxe2x80x94 in the chain thereof.
It is also preferred that in general formula (1), ring C represents phenyl group or piperidyl group,
X represents an alkylene group having 1 to 6 carbon atoms,
R3 represents a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s) or an amidino group, which may have a substituent(s),
when R3 has a substituent(s), the substituent is an alkyl group having 1 to 6 carbon atoms or pyridyl group, and
R8 and R9 may be the same or different from each other and they each represent hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group.
It is also preferred that in general formula (1), ring A represents phenyl group,
R1 represents hydrogen atom, chloro group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, amino group, which may have a substituent(s), hydroxyl group, which may have a substituent(s) or an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s),
when R1 has a substituent(s), the substituent is hydroxyl group, phosphono group, carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, piperazinecarbonyl group, an alkylpiperazinecarbonyl group having 6 to 10 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms,
ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 represents chloro group or bromo group,
ring C represents phenyl group or piperidyl group,
R3 represents a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), or amidino group, which may have a substituent(s),
when R3 has a substituent(s), the substituent is an alkyl group having 1 to 6 carbon atoms or pyridyl group,
R4, R5, R6, R7, R8 and R9 may be the same or different from one another and they each represent hydrogen atom, a halogeno group, trifluoromethyl group, methoxyl group or hydroxyl group, and
X represents an alkylene group having 1 to 6 carbon atoms.
It is also preferred that in general formula (1), ring A represents phenyl group,
R1 represents hydrogen atom, chloro group, amino group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, a morpholinealkyl group, hydroxyl group, methyl group, phosphonoethyl group, morpholinecarbonylethyl group, piperazinecarbonylethyl group, isopropylpiperazinecarbonylethyl group, methanesulfonylaminoethyl group or hydroxypropyl group,
ring B represents phenyl group or thiophene group,
R2 represents chloro group or bromo group,
ring C represents phenyl group or piperidyl group,
R3 represents isopropyl group, cyclohexyl group, pyridyl group, 1-methyl-1H-imidazol-2-yl group, 1, 3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, 1-pyrrolidinylcarbonyl group, 2,5-dihydro-1H-pyrrol-1-yl(imino)methyl group or 1-iminoethyl-piperidin-4-yloxyl group,
R4, R5, R6, R7, R8 and R9 may be the same or different from one another and they each represent hydrogen atom or a halogeno group,
X represents methylene group or ethylene group, and
Z1 and Z2 each represent hydrogen atom.
It is also preferred that in general formula (1), X represents an alkyl group having 1 to 6 carbon atoms.
It is also preferred that in general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 represents a halogeno group, an alkyl group having 1 to 6 carbon atoms, trifluoromethyl group or an alkoxyl group having 1 to 10 carbon atoms, and
R6 and R7 each represent hydrogen atom.
It is also preferred that in general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms and a substituent or a heteroaryl group having 4 to 10 carbon atoms,
R2 represents a halogeno group, an alkyl group having 1 or 2 carbon atoms, trifluoromethyl group or an alkoxyl group having 1 to 3 carbon atoms, and
R6 and R7 are each hydrogen atom.
It is also preferred that in general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 represents a chloro group or bromo group, and
R8 and R9 are each hydrogen atom.
It is also preferred that in general formula (1), ring B represents phenyl group, naphthyl group, pyridyl group or thiophene group.
It is also preferred that in general formula (1), ring C represents an aryl group having 6 to 10 carbon atoms or piperidyl group,
R3 represents a halogeno group, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), pyridyl group, nitro group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, a dialkylamino group, amidino group, which may have a substituent(s) or piperidyloxyl group, which may have a substituent(s), and
R8 and R9 are each hydrogen atom
It is also preferred that in general formula (1), ring C represents phenyl group or 4-piperidyl group,
R3 represents a halogeno group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, 4-pyridyl group, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), nitro group, amino group, dimethylamino group, amidino group, which may have a substituent(s) or a piperidyloxyl group, which may have a substituent(s), and
R8 and R9 are each hydrogen atom
It is also preferred that in general formula (1), ring A represents phenyl group,
ring B represents phenyl group or thiophene group,
R2 represents chloro group or bromo group,
ring C represents phenyl group or piperidyl group,
R3 represents pyridyl group, and
X represents methylene group.
It is also preferred that in general formula (1), ring A represents phenyl group,
ring B represents phenyl group, pyridyl group, thiophene group or naphthyl group,
R2 represents a halogeno group, an alkyl group having 1 to 6 carbon atoms, trifluoromethyl group or an alkoxyl group having 1 to 10 carbon atoms,
ring C represents phenyl group or piperidyl group,
R3 represents a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a halogeno group, pyridyl group, nitro group, an alkyl group having 1 to 6 carbon atoms, which may have a substituent(s), an amino group, a dialkylamino group, amidino group, which may have a substituent(s) or piperidyloxyl group, which may have a substituent(s), and
X represents methylene group.
It is preferred that in general formula (1), ring A represents phenyl group,
ring B represents phenyl group or thiophene group,
R2 represents chloro group or bromo group,
ring C represents phenyl group or piperidyl group,
R3 represents pyridyl group, and
X represents methylene group.
Typical processes for producing compounds (1) of the present invention will be described below. For example, a compound of general formula (1), wherein ring A represents phenyl group, which may have a substituent(s) and X represents an alkyl group having 1 to 6 carbon atoms, can be produced by a process described below.
Namely, a compound (4) can be obtained by reacting an amino acid ester (2) with, for example, a 2-nitrobenzyl halide (3) in the presence of a base such as sodium hydrogencarbonate in ethanol as the solvent. A compound (6) can be derived from the obtained compound (4) by reacting it with, for example, an acid halide (5) in the presence of a base such as triethylamine in a solvent such as dichloromethane. A compound (7) can be derived from the obtained compound (6) by hydrolyzing it in the presence of a base such as sodium hydroxide in a solvent such as tetrahydrofuran and then reacting the obtained product in the presence of a catalyst such as palladium/carbon in a solvent such as ethanol in, for example, hydrogen atmosphere. A compound (8) can be derived from the obtained compound (7) by reacting it with a condensing agent in the presence of a base such as triethylamine in a solvent such as dimethylformamide to conduct the intramolecular condensation. A benzodiazepine derivative (10) can be derived from the obtained compound (8) by reacting it with a compound (9) in the presence of a base such as sodium hydride in a solvent such as dimethylformamide.
By changing the starting material (3), compounds of general formula (1) wherein ring A is other than phenyl group, such as an aryl group, a heteroaryl group or cycloalkyl group can be synthesized. 
The compound (6) can be converted to compound (11) by reacting it in the presence of a catalyst such as palladium/carbon in, for example, ethyl acetate in, for example, hydrogen atmosphere. Then a compound (13) can be obtained by reacting the compound (6) with a reducing agent such as sodium triacetoxyborohydride and a compound such as (12) in the presence of an acid such as acetic acid in a solvent such as dichloromethane. The obtained compound (13) can be converted to a benzodiazepine derivative (14) by the hydrolysis in the presence of a base such as sodium hydroxide in a solvent such as tetrahydrofuran followed by the intramolecular condensation with a condensing agent in the presence of a base such as triethylamine in a solvent such as dichloromethane. 
The compounds of general formula (1) produced as described above and salts thereof can be isolated by the purification by a well-known separation/purification method such as extraction, concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, redissolution or various chromatographic techniques.
The salts of the benzodiazepine derivatives of general formula (1) are pharmaceutically acceptable ones. When the formula has a basic group, the salts of them are acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc.; and organic acids such as formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid, etc. When the formula has an acidic group such as carboxyl group, the salts of them are base addition salts such as ammonium salts, salts with alkali metals such as sodium and potassium, etc., alkaline earth metals such as calcium and magnesium, etc., aluminum, zinc, organic amines such as triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, etc., basic amino acids such as arginine and lysine, etc.
The compounds of general formula (1) in the present invention include their solvates such as hydrates and alcohol adducts thereof.
The compounds of general formula (1) and salts thereof are administered as they are or in the form of various pharmaceutical compositions to patients. The dosage forms of the pharmaceutical compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets and depots. They can be prepared with ordinary preparation assistants by an ordinary method. For example, the tablets are prepared by mixing the benzodiazepine derivative, the active ingredient of the present invention, with known adjuvants such as inert diluents, e.g. lactose, calcium carbonate and calcium phosphate, binders, e.g. acacia, corn starch and gelatin, extending agents, e.g. alginic acid, corn starch and pre-gelatinized starch, sweetening agents, e.g. sucrose, lactose and saccharin, corrigents, e.g. peppermint and cherry, and lubricants, e.g. magnesium stearate, talc and carboxymethyl cellulose.
The blood-coagulation inhibitor containing one of the benzodiazepine derivatives of general formula (1) and salts thereof is usable for preventing or treating cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral arterial occlusive disease; deep vein thrombosis; disseminated intravascular coagulation; thrombus formation after an artificial blood vessel-forming operation or an artificial valve substitution; reocclusion and restenosis after a coronary artery bypass grafting; reocclusion and restenosis after a reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
When the benzodiazepine derivatives represented by general formula (1) are used as the anticoagulants, they can be administered either orally or parenterally. The dose which varies depending on the age, body weight and conditions of the patient and the administration method is usually 0.01 to 1,000 mg, preferably 0.1 to 50 mg, a day for adults in the oral administration, and 1 xcexcg to 100 mg, preferably 0.01 to 10 mg, in the parenteral administration.